The recent outbreak of Ebola virus in West Africa has emphasized the need for understanding the immune response to acutely infectious, deadly viruses and developing immunotherapeutic options for treating or preventing infection. It is thought that inhibitory receptors attenuate the responses of cytolytic lymphocytes, such as Natural Killer (NK) and CD8+ T cells, to virally infected cells. Indeed, this is the case in the context of chronic viral infections. However, in our preliminary studies we have found that Nkg2a, an inhibitory receptor that is expressed on activated CD8+ T cells and on a subset of NK cells, promotes the response to an acute, deadly viral infection caused the mouse orthopoxvirus Ectromelia (ECTV). Remarkably, Nkg2a does not limit the immune response like other inhibitory receptors, but rather sustains CD8+ T cell responses against ECTV by preventing activation-induced cell death (AICD) of virus-specific CD8+ T cells in a cell intrinsic manner. This observation provides a new, provocative point of view for understanding the immunology of acute, lethal viral infections; it suggests that inhibitory receptors, or at least some of them, ma be essential for effective CD8+ T cell responses and hence may lead to new avenues for therapeutic intervention. We will explore this hypothesis using newly generated Nkg2a-/- mice through the following aims. In specific aim 1, we will determine whether Nkg2a-/- mice CD8+ T cell are susceptible to AICD exclusively within the milieu of an acute lethal virus infection that presumably generates a highly inflammatory cytokine micro-environment or during TCR-mediated activation in general. Moreover, we will ascertain whether anti- apoptotic cytokines can rescue Nkg2a-/- CD8+ T cells in vivo and whether cell-extrinsic mechanisms contribute to the Nkg2a-/- CD8+ T cell defect. In specific aim 2, we will test the impact of Nkg2a on the proliferation and function of virus-specific memory CD8+ T cells during acute lethal poxvirus infection. We hypothesize that Nkg2a augments the magnitude of the memory CD8+ T cell response and long term immunity to ECTV. In specific aim 3, we will focus on another inhibitory receptor structurally related to Nkg2a, known as Klrg1, which we have found to contribute to host defense against ECTV in synergy with Nkg2a. Since Klrg1 and Nkg2a share very similar expression patterns, we will ask whether Klrg1 primarily functions to maintain CD8+ T cell and perhaps NK cell numbers during the anti-ECTV response by preventing AICD or, alternatively, whether Klrg1 prevents activated CD8+ T cells and/or NK cells from discharging excessive lytic mediators and inflammatory cytokines that cause immunopathology. Based on our substantial record in the field of inhibitory receptors, our newly generated Nkg2a-/- mouse line and our expert collaborators in poxvirus biology, we are in a strong position to successfully pursue this paradigm-shifting view of inhibitory receptor function during anti-viral responses.